The panel did not have substantial concerns about the risk of liver disease associated with the drug and agreed the data did not indicate a significant signal for hepatoxicity, but that hepatic adverse events should be monitored after approval. The one case of what was thought to be probable drug-induced liver injury in clinical trials was later considered more likely to be autoimmune hepatitis, provided "substantial reassurance" that this was not drug-related, although it could not be completely ruled out, they said.
The panel also recommended that rates of breast cancer in women be monitored after approval. A numerical increase in breast cancers among those on dapagliflozin was a concern at the first meeting, although the FDA concluded that the data on the breast cancer risk associated with dapagliflozin were inconclusive and insufficient.
The companies are planning to follow these safety issues in studies that include pharmacoepidemiology studies underway in Europe – which are monitoring for cancer, acute liver injury, and severe urinary tract infection complications – and a cardiovascular outcomes study with a planned enrollment of 17,150 patients with type 2 diabetes and established CV disease or at least two CV risk factors. Enrollment for the latter study – the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI-58) study – in Europe has already begun.
The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.
In studies, dapagliflozin lowered hemoglobin A1c at the 5-mg and 10-mg once-daily doses and also was associated with decreases in fasting blood sugar, small decreases in systolic blood pressure (in hypertensive patients) and body weight, and LDL-cholesterol elevation. Adverse events associated with treatment include a higher rate of genital infections, volume depletion, and polyuria.
Since November 2012, dapagliflozin has been approved in the European Union, Australia, Mexico, New Zealand, Brazil, and Argentina. To date, over 35,000 people worldwide have been treated with dapagliflozin, according to Bristol-Myers Squibb. If approved, BMS and AstraZeneca plan to market dapagliflozin as Forxiga. A decision on approval is expected by Jan. 11, 2014.